This invention relates to a non-invasive apparatus and methods for in vivo monitoring of the concentration levels of various blood analytes within a living subject, using optical absorption spectrophotometry. The device and methods may be used to simultaneously monitor several analytes found in the blood outside of a laboratory setting. The device and methods are able to resolve analytes down to approximately one mg/dL. Further, the device and methods are able to measure all blood analytes present at approximately one mg/dL, including glucose and lactate, for example.
Information concerning the concentrations of blood analytes is widely used to assess the health characteristics of people. For example, lactate is becoming the measurement of choice in sports and coaching to assess levels of conditioning for athletes and to prevent over-training. Lactate threshold and other related parameters are used to assess the aerobic and anaerobic status of athletes, are correlated to athletic performance, and may be used to “rank” athletes according to actual performance history. Lactate monitoring, as used in athletics, may also be useful for Military Academies, Army boot camps, and other physical training operations to assess the physical condition of trainees, to improve training programs, and to evaluate the effectiveness of training regimens on specific individuals. Lactate is also widely used to assess the medical condition of injured people. When serum lactate elevates after an injury, whether or not the lactate clears is correlated strongly with mortality, thus, measurement of serum lactate levels is a key tool in assessing treatment.
Likewise, the monitoring of blood glucose has long been an important tool in controlling diabetes in diabetic patients. Diabetes is a high maintenance disease, generally requiring several measurements of blood glucose daily. At present, this is typically accomplished using a glucometer, in which a fresh blood sample must be obtained for each measurement. Each measurement typically requires a new “test strip” for receiving the blood sample, the test strips characteristically being relatively expensive. Such measurements are often painful, cumbersome, and moderately time-consuming. The method of testing blood glucose using a test strip is generally referred to as the “finger stick” method. It specifically involves applying a drop of blood to the test strip, the test strip using molecular sieves to block molecules larger than molecular weight of about 200. The sieves consequently block, for example, large glycosylated proteins from being included in the blood glucose measurement. Due to the inconvenience and expense, many diabetic patients do not monitor their blood glucose levels as often as recommended. About 16 million diabetic patients in the United States need to regularly monitor their blood glucose levels.
A non-invasive device enabling painless and convenient monitoring of blood glucose would be of great benefit to diabetic patients. The relative ease of measurement may contribute to a more regular blood glucose monitoring regime by diabetic patients. Various attempts have been made at a blood glucose measurement device using spectroscopy. However, those attempts have generally had problems with “baseline drift” of unknown origin. It is hypothesized that the absorption method used in most spectroscopy devices for measuring glucose in the blood measures all glucose in the blood, both the bound glucose and the free glucose. For the purpose of diabetes management, measurement of the concentration of free glucose is desired. That is, the concentration of free glucose in the blood is generally recommended to be in the range of 80 mg/dL and 120 mg/dL. A diabetic patient will measure their blood glucose level to determine whether the level is within the recommended range. If the blood glucose level is outside of the recommended range, the diabetic patient will typically inject insulin to reduce the blood glucose level. Again, it is the free glucose concentration level that is relevant to determining whether the patient's blood glucose concentration is within the recommended range. Because absorption techniques may measure both free and bound glucose levels as one measurement, there may be an overstatement of the blood glucose level that results in faulty treatment by the patient. The molecular sieves of the test strip glucometers described above correct for the possibility of measuring bound and free glucose by preventing the bound glucose, with a relatively high molecular weight, from passing through the sieve.
It is notable, however, that the finger stick methods take only one measurement of the glucose concentration level in the blood and, for a series of measurements, require a series of blood samples, generally obtained by a series of finger pricks. Consequently, the finger stick methods do not offer an appealing method of continuous measurement of blood glucose concentration in the blood. Continuous measurement of blood glucose levels enable near instant recognition of abnormal blood glucose levels whereas a series of individual measurements inevitably includes periods of time where the precise blood glucose level is unknown. Thus, a diabetic patient may be better able to control blood glucose levels. It may also assist the person in adjusting their lifestyle, diet, and medication for optimum benefits. Providing the easy, non-invasive, and optionally continuous monitoring provides a great improvement in the treatment of the diabetes and allows the treatment to be tailored to the individual.
Many other blood analytes with concentrations similar to or greater than lactate and glucose are of fundamental importance; for example, hemoglobin and its sub-types, albumin, globulins, electrolytes, and others. Hemoglobin is important especially in the monitoring of anemia caused by various various factors such as HIV infection and chemotherapy. Anemia treatments need frequent monitoring of hemoglobin to assess effectiveness of various treatments such as Epoetin-Alpha therapy.
Spectrophotometry provides a useful method for determining the presence of analytes in a system. A typical spectrometer exposes a dissolved compound to a continuous wavelength range of electromagnetic radiation. The radiation is selectively absorbed by the compound, and a spectrograph is formed of radiation transmitted (or absorbed) as a function of wavelength or wave number. Absorption peaks are usually plotted as minima in optical spectrographs because transmittance or reflectance is plotted with the absorbance scale superimpose, creating IR absorption bands.
At a given wavelength the absorption of radiation follows Beers' Law, an exponential law of the form:A=εCb Where: A=absorbance=−log10(t; ).                t=fraction of radiation transmitted (or reflected).        ε=molar extinction coefficient, cm2/mol.        C=concentration, mol/cc.        b=thickness presented to radiation, cm.        
The wavelengths of maximum absorption, λmax, and the corresponding maximum molar extinction coefficient, εmax, are identifying properties of a compound. Radiation causes excitation of the quantized molecular vibration states. Several kinds of bond stretching and bond bending modes may be excited, each causing absorption at unique wavelengths. Only vibrations that cause a change in dipole moment give rise to an absorption band. Absorption is only slightly affected by molecular environment of the bond or group. Nevertheless, these small chemical shifts may aid in uniquely identifying a compound. A “fingerprint region” exists between 42 and 24 THz (1400 and 800 cm−1) because of the many absorption peaks that occur in this region. It is virtually impossible for two different organic compounds to have the same infrared (IR) spectrum, because of the large number of peaks in the spectrum. While the peaks and valleys are the traditional features used in this type of spectrophotometry, the overall shape of the spectra may also provide useful information, especially in mathematically separating mixed spectra where more than one analyte is present.
In addition to the IR absorption bands, absorption peaks also occur in the near-IR region (700-2500 nm). Absorptions in this region are most often associated with the overtone and combination bands of the fundamental molecular vibrations of —OH, —NH, and —CH functional groups that are also seen in the mid IR region. As a result, most biochemical species will exhibit unique absorptions in the near-IR. In addition, a few weak electronic transitions of organometallic molecules, such as hemoglobin, myoglobin, and cytochrome, also appear in the near-IR. These highly overlapping, weakly absorbing bands were initially perceived to be too complex for interpretation and too weak for practical application. However, recent improvements in instrumentation and advances in multivariate chemometric data analysis techniques, which may extract vast amounts of chemical information from near-IR spectra, allow meaningful results to be obtained from a complex spectrum. Absorption bands also occur in the visible range (400-700 nm). For example, hemoglobin and bilirubin absorb strongly in this region.
Traditionally, Near Infrared Spectroscopy (NIRS) has been used to estimate the nutrient content of agricultural commodities. More recently NIRS has become widely applied in the food processing, chemical, pulp and paper, pharmaceutical, polymer, and petrochemical industries.
Invasive devices and methods of quantifying and classifying blood analytes using IR and other optical spectrophotometry methods are very commonly known. Invasive procedures are those where a sample such as blood is taken from the body by puncture or other entry into the body before analysis. Invasive procedures are undesirable because they cause pain and increase the risk of spread of communicable, blood-borne diseases. Further, after the invasive collection of body samples, these samples may need to be further prepared in the laboratory by adding water or ions to the samples to increase the accuracy of the spectrophotometry readings. Thus, these commonly known devices and methods are often only suitable for use under laboratory in vitro conditions and are too difficult to be practically applied in athletic training and military situations. It is noted, of course, that the finger stick method of measuring blood glucose concentration levels using a glucometer has been adapted for home use.
Recently, non-invasive devices for monitoring levels of blood analytes using infrared spectroscopy have been developed. For example, U.S. Pat. No. 5,757,002 by Yamasaki relates to a method of and an apparatus for measuring lactic acid in an organism in the field of sports medicine or exercise physiology. Also, U.S. Pat. No. 5,361,758 by Hall relates to a non-invasive device and method for monitoring concentration levels of blood and tissue constituents within a living subject.
Previous non-invasive devices and methods typically require time-consuming custom calibrations to account for the differences between individuals and environmental factors which cause variation in energy absorption. There are several factors that may result in variation in energy absorption; for example, environmental factors such as temperatures and humidity that may affect the equipment, and individual factors such as skin coloration, skin weathering, skin blemishes or other physical or medical conditions. This need for custom calibration to each individual makes it impractical to use previous devices on demand in training situations or at the scene of accidents. A universal or self-calibrating device that is capable of taking into account these variations would be useful.
Further, many previous non-invasive devices and methods accurately measure only a single blood analyte at a time. Most typically, the devices are designed to measure blood glucose. To measure a different analyte, the device must be reprogrammed or otherwise altered. Even with such reprogramming or alteration, the devices may not typically measure the results of two or more analytes at the same time without significant inaccuracies. Each analyte in the blood sample contributes a unique absorption pattern to the overall infrared spectrum, governed by the unique set of molecular vibrations characteristic of each distinct molecular species. The infrared spectral range extends from 780 nm to 25,000 nm and is commonly subdivided further into the near-infrared and mid-infrared regions. Most devices obtain an measurement of an analyte by using only a small portion of the IR spectrum reflecting the particular analyte of interest. In those devices that do attempt to use a wider spectrum to obtain multiple analyte readings, relatively ineffective methods are used to separate and account for multiple analyte spectral interferences, leading to decreased accuracy. Thus, there exists a need for a device that may successfully use a wider spectrum to accurately and simultaneously isolate and determine the concentrations of multiple analytes.
IR spectroscopy typically involves radiating light onto a portion of tissue for either transmission through the tissue or reflection from the tissue. The transmitted or reflected radiation is then analyzed to determine concentrations of analytes. However, the radiation that is transmitted or reflected is not just transmitted through or reflected from the blood, but instead includes transmissions or reflection from the skin, subdermal tissue, and blood. Thus, the received radiation is a mixture of absorption signals from skin and tissues and blood. The signals contributed by the skin and tissues make it difficult to accurately measure the presence of blood analytes. These signals need to be separated to eliminate the effects of skin and tissue in order to measure the analytes in the blood. Previous non-invasive devices and methods were unable to separate blood-related readings from body tissue readings. Therefore, there is a need for a device capable of separating the blood-related component of the signal from the tissue component.
One method of achieving the separation of a blood-related component of the signal is to accept only the portion of the mixed signal which has a pulse synchronized with the heart pulse, known as a pulsatile technique or synchronous detection. The pulsatile signal is the time varying portion of the whole signal that is synchronized with the heart beat. This method presumes that the pulsations come from the movement of arterial blood or closely related volume and allows a signal associated with the blood to be separated from that of tissue. The synchronous method is widely used for separating blood-related components in pulse oximeters.
Another possible method for achieving separation of the blood related components of the signal from tissue and skin related components uses a hematocrit-type method to determine the portion of the signal associated with the blood. The hematocrit is the proportion, by volume, of the blood that consists of red blood cells. The hematocrit is typically measured from a blood sample by an automated machine that makes several other measurements at the same time. Most of these machines do not directly measure the hematocrit, but instead calculate it based on the determination of the amount of hemoglobin and the average volume of the red blood cells. Using a hematocrit method generally is faster than using a synchronous method because there is no need to wait for heart beats. Further, there is less signal loss associated with hematocrit methods than with the synchronous method, the synchronous method removing some blood associated signal unnecessarily.
Finally, many non-invasive devices for in vivo monitoring of blood analyte concentrations do not allow for an ambulatory application. They typically utilize permanent equipment set up in a laboratory or other test site, which makes it impossible to use while away from the laboratory or other test site. Thus, there is a need for a device that may be easily transported and used away from the laboratory. The device would preferably not interfere with the user's normal functioning and would greatly increase the utility and range of analyte concentration monitoring beyond the laboratory setting.